Chemical compounds

ABSTRACT

1. A compound selected from the group consisting of:   AND ACID ADDITION SALTS THEREOF WHEREIN R is selected from the group consisting of hydrogen, alkyl having up to 6 carbon atoms, benzyl, or cycloalkyl having up to 8 carbon atoms; Y is selected from the group consisting of hydrogen, chloro, or bromo; and X and X&#39;&#39; are selected from the group consisting of hydrogen, chloro, or bromo. 2. A compound selected from the group consisting of:   AND ACID ADDITION SALTS THEREOF WHEREIN R is selected from the group consisting of hydrogen and alkyl having up to 6 carbon atoms.

United States Patent [191 Engelhardt 1 Nov. 25, 1975 1 CHEMICAL COMPOUNDS [75] Inventor: Edward L. Engelhardt, Gwynedd Valley, Pa.

[73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: July 25, I963 [21] Appl. No.: 297,710

Related U.S. Application Data [63] Continuation-impart of Ser. No. 215,770, Aug. 9, 1962, abandoned, which is a continuation-in-part of Ser. No. 140,223, Sept. 25, 1961, abandoned, which is a continuation-in-part of Ser. No. 120,835, May 24, 1961, abandoned.

[52] U.S. CI. 260/570.8 TC; 260/326 R; 260/438.1', 260/465 R; 260/465 K;

260/471 C; 260/48213', 260/50l.1; 260/518 R; 260/518 A;260/519; 260/543 F; 260/551 CN; 260/556 A; 260/558 R; 260/559 R; 260/561 R; 260/611 R; 260/566 F; 260/570.9; 260/590;

260/618 F: 260/649 R; 260/668 F;

OTHER PUBLICATIONS Derwent Belgian Patents Report, Vol. 618, Feb. 15, 1960, p. C32.

Primary Examiner-R. V. Hines Attorney, Agent, or FirmHarry E. Westlake, Jr.; Thomas E. Arther; James A. Arno EXEMPLARY CLAIM 1. A compound selected from the group consisting of:

CH CH CH NHR and X XI CH CH CH NHR and acid addition salts thereof wherein R is selected from the group consisting of hydrogen, alkyl having up to 6 carbon atoms, benzyl, or cycloalkyl having up to 8 carbon atoms; Y is selected from the group consisting of hydrogen, chloro, or bromo; and X and X are selected from the group consisting of hydrogen, chloro, or bromo.

2. A compound selected from the group consisting of:

CHCH CH NHR and CH CH CH NHR and acid addition salts thereof wherein R is selected from the group consisting of hydrogen and alkyl having up to 6 carbon atoms.

6 Claims, No Drawings CHEMICAL COMPOUNDS This application is a continuation-in-part of application Serial No. 215,770 filed August 9, 1962 and abandoned July 29, 1963, which in turn is a continuation-inpart of application Serial No. 140,223 filed September 25, 1961 and abandoned April 26, l963, which in turn is a continuation-in-part of application Serial No. 120,835 filed May 24, 1961 and abandoned November 8. 1962.

This invention relates to new derivatives of dibenzocycloheptenes and to processes for making them. More particularly, the invention includes SH-dibenzo[a,d]-cycloheptenes and 10,1 l-dihydro-SH-dibenzo[a,d}cycloheptenes which are substituted at their carbon atom with an aminopropyl or an aminopropyli dene radical. The amino entity may be either primary or secondary and if secondary, the substituent may be either a lower alkyl or alkenyl radical having up to 6 carbon atoms, cycloalkyl having up to 8 carbon atoms or an aralkyl radical. The dibenzocycloheptene nucleus may be further substituted. The invention also includes the intermediates used for obtaining these products. Also included are derivatives such as acyl derivatives which yield the active compound under physiological conditions.

The novel compounds of the invention may be represented by the general formulae in which R may be hydrogen or a cyano radical; R may be hydrogen or an alkyl or alkenyl radical having up to 6 carbons, either straight or branched chain, or cycloalkyl having up to 8 carbons or aralkyl groups such as benzyl; Y may be hydrogen or halogen, preferably bromine or chlorine; X and X are similar or dissimilar and are selected from hydrogen, an alkyl group having up to 6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, an acyl group having up to 4 carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino, an alkylamino group having up to 4 carbon atoms, a dialkylamino group having up to 8 carbon atoms, an acylamino group having up to 4 carbon atoms, a perfluoroacylamino group having up to 4 carbon atoms, an alkylsulfonylamino group having up to 4 carbon atoms, halogen (fluorine, chlorine, bromine or iodine), hydroxyl, an alkoxyl group having up to 4 carbon atoms, a perfluoroalkoxyl group having up to 4 carbon atoms, cyano, carboxy, carbamoyl, analkylcarbamoyl group having up to 5 carbon atoms, a dialkylcarbamoyl group having up to 9 carbon atoms, a carbalkoxy group having up to 6 carbon atoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, a perfluoroalkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, a perfluoroalkylsulfonyl group having up to 4 carbon atoms, sulfamoyl, an alkylsulfamoyl group having up to 4 carbon atoms, or a dialkylsulfamoyl group having up to 8 carbon atoms. More than one of these substituents may be on each benzenoid ring. The compounds may have substituents on the propyl or propylidene chain such as lower alkyl radicals, preferably having from 1 to 4 carbon atoms.

The dotted line between the 10 and l l carbon'atoms indicates that the compounds may be saturated or unsaturated at this location, the saturated compound being identified by the 10,] l-dihydro designation.

The compounds represented by the above formulae wherein R is hydrogen are useful in the treatment of mental disorders since they are anti-depressants and serve as mood elevators or psychic encrgizers. For this purpose, the daily dosage is within the range of 5 mg. to 250 mg., preferably taken in divided amounts over the day. The compounds are preferably administered in the form of their acid addition salts and these salts are included in the scope of this invention. The compounds represented by the above formulae wherein R is a cyano radical are useful as intermediates in the preparation of the active compounds.

The compound I and II differ from each other in that the side chain of compounds I is attached to the nucleus by a double bond. Because of this process for making compounds I will not be suitable for making compounds II.

To obtain the primary amines of compounds I, it is necessary to employ a different method from that suit able for obtaining the primary amines of compounds II. For those primary amines of compounds I, the following general method may be followed:

flbmo auccininida alkali metal cyanide This method A begins with the known ketonc which may be prepared by using the process described by A.C. Cope et al.. entitled "Cyclic Polyolefins. XV. lmethylene-2.3,6.7-dibenzocycloheptatriene." appearing in J.A.C.S. 73. 1673-4678 (1951). Or the other starting compounds. and particularly those having sub stituents on the benzene rings may be made by following the teachings of T.W. Campbell et al. in an artical entitled Synthesis of 2'-acetamido-2.3:6.7-dibenzotropilidene and 2-acetamido-9.9-dimethylfluorene," appearing in Helv. Chim. Acta 36. l489-l499 (1953). The preparation of the starting compounds having a bromine substituent in either the 10 or ll positions may be done as described by W. Treibs and H. J. Klinkhammer, Chemische Berichte 84. 671-679 (1951). The preparation of the starting compounds having a chlorine substituent in either the 10 or ll positions may be done as described in the examples hereinafter.

Method A involves the attachment of an ethylidene chain to the S-carbon of the nucleus and its subsequent expansion to a propylidene chain having a terminal amino group. The Grignard reagent and the reaction using it are conventional. an inert solvent such as ether is used and the reaction is completed at refluxing temperature. The Grignard adduct is hydrolyzed in the usual manner but it is preferable that it be under ap proximately neutral conditions such as produced by the Method A (I) as a primary mine addition of ammonium chloride solution. The dehydration step which next follows is carried on preferably by a chemical dehydrating agent such as acetyl chloride. acetic anhydride or trifluoroacetic anhydride which can subsequently be removed by evaporation. N- bromosuccinimide is used for the next step as it isa selective brominating agent and avoids adding bromine to the olefinic linkage. This bromination is preferably carried on at the refluxing temperature of a low boiling inert solvent such as benzene. A substantial excess of N-bromosuccinimide is to be avoided, particularly with compounds of the 10,1 ldihydro series. The resulting succinimide precipitates and is removed.

"The substitution of the cyanide group for the bromine will occur at room temperature but to hasten it heat is preferably applied. The resulting cyanoethylidene derivative in method A is then isolated by evaporation of the solvent and is then subjected to the reduction step. To avoid simultaneous reduction at the aliphatic double bond. it is best to use a chemical reducing agent such as lithium aluminum hydride in the presence of anhydrous ether. After hydrolysis as by the addition of a caustic alkali solution. the ether layer is recovered and the product obtained from it by distillation.

The primary amine which is so obtained in method A can readily be converted to a secondary amine type of compounds I by the following reactions:

(RCO) (I) at! a primary-mine CHCHZCHZNHZ HCH CH NHCH R (I) as a secondary amino ln method B, R can be alkyl, alkenyl or phenyl.

The conversion to the amide is readily carried out by the addition of an acyl halide or anhydride, such as acetic anhydride. This is carried on at room temperature with stirring or by heating. The amide is isolated by removal of the excess acylating agent and the reduction is carried out by the use of a metal hydride as explained above to avoid reduction of the olefinic double bond.

As noted above, method A is useful to obtain compounds I having an olefinic linkage to the side chain. To obtain the compounds of type ll, the following series of reactions may be carried out:

Method B in method C, R may be an alkyl or an aralkyl radical.

Method C, in general, involves the initial attachment of an alkoxy or aralkoxy propyl radical at the S-carbon of the nucleus by a Grignard reaction, the simultaneous reduction of the S-hydroxy compound and conversion of the alkoxy or aralkoxy group to an iodo radical and then the replacement of this iodo radical with an amino HQI-MQCH CH CH OR x o i H CH CH CH OR H 011 CH I a HZCHZCHZRHZ (II) as a primary amino 3 13111 or hqdrolylil Method 0 lower alkyl radical having up to 6 carbons. The result-V ing Grignard adduct is hydrolyzed preferably under neutral conditions as by using an ammonium chloride solution. The resulting product is recovered from the solvent ,by evaporation and is treated with hydriodic acid in the presence of a solvent such as acetic acid or acetic anhydride. The iodinated compound is extracted into asolvent such as benzene and recovered therefrom by evaporation of the solvent. The addition'to this iodo compound of the potassium phthalimide is carried on with a solvent's'uch as dimethylformamide and after the,

complete'addition, slight heat may be applied to in crease the reaction rate. The phthalimido compound is isolated by extraction.

The subsequent reaction with hydrazine hydrate is carried on in methanol or ethanol and heat may be applied up to the refluxing temperature to hasten the reaction. The phthalhydrazide is separated and the primary amino compound ll is recovered from the solu- 20 tion. instead of employing hydrazinolysis. the

phthalimido compound can be converted to the amine by hydrolysis. V

This produces the aminopropyl compounds II as a primary amine. and they can be converted to a secondary amine by the following procedure:

H CH CH I I-CHRR' (II) as a secondary mine In method D, the primary amine ll is combined with a ketone or an aldehyde of the above structure wherein R is hydrogen or a lower alkyl radical and R may be hydrogen. alkyl and cycloalkyl. R and R may also be linked together throughian alkylene chain to form a cyclic ltctone. The reaction is carried out in a solvent such as benzene or toluene and heated to refluxing.

temperature. The resulting alkylidene or cycloalkylidene aminopropyl compound is then recovered by evaporating off the solvent and it is reduced by catalytic hydrogenation to the resulting secondary aminopropyl compound when Y is hydrogemwhen Y is halogen, the reduction may be accomplished with 'a metal hydride as described in method B. Instead of isolating the intermediate compound when Y is hydrogen, the primary amine and the selected carbonyl compound can be dissolved in a suitable solvent such as a lower alcohol. and catalytic hydrogenation carried out.

, The primary amine ll may also be converted to the secondary amine ll by following method B..Likewise, the primary amine I may be converted to the secondary amine l by following method D. a

The foregoing methods for preparing the secondary amines l and ll are especially suited to those cases where groups larger than methyl are present. Where methylor ethylaminopropylidene and methylor ethylaminopropyl substituents are desired. they are conveniently prepared from the corresponding dialkylreduction He liked D 7 amino compounds by treatment with a cyanogen halide. This monodealkylation process as applied to compounds I and ll may be represented as follows:

Y I l l l' Method B alkyl l t C liLH C H iku (1) as a secondary amino (II) as a secondary amino Method F propylidene)-l0,l l-dihydro-5H-dibenzo[a.d]cycloheptenes employed as starting compounds in method E may be prepared as described in Belgian Patents 578,l22 and 584.06l, respectively.

The 5-(3-dialkylaminopropyl)-5H-dibenzo[a,dl-

cycloheptenes and 5-(3-dialkylaminopropyl)-l0.l ldihydro-SH-dibenzo[a,dlcycloheptenes may be prepared by condensing a S-halo derivative of the selected 5H-dibenzo[a,d]cycloheptene with a dialkylaminopropyl Grignard reagent. This may be represented as follows:

' conventional procedures. The Grignard reagent may be hydropyran. Z-methyltetrahydrofuran and tetrahydroprepared in a conventional solvent such as ether, tetrafuran and the like. but tetrahydrofuran is preferred. These solvents may remain present during the reaction.

As the reaction is exothermic. the reactants should be combined very slowly or they may be combined more rapidly ifexternal cooling is applied to the reac- 2 maximum yield. The solvent can be removed by distilling it off under reduced pressure. The mixture is di luted with benzene and the excess Grignard reagent is hydrolyzed. As the desired end product is soluble in benzene. this layer is separated and the product isolated therefrom. 7

Further purification can be achieved by extraction with dilute acid which is then neutralized with alkali. The product is recovered therefrom with a solvent such as benzene or hexane which is then distilled off. The base of the product can be converted to a salt by the addition of such commonly used acids as hydrochloric acid, phosphoric acid, acetic acid. maleic acid and the like. To make the hydrochloride salt. it is preferable to add a solution of hydrogen chloride to a solution of the end product in dry alcohol.

A variation of method C to produce compounds ll as the primary amines involves starting with the S-halo (preferably chloro or bromo) derivatives of the selected 5H-dibenzo[a.dIcycloheptene. This method involves the following series of steps:

ll EH CH CH ORV as in method C Method G The R portion of the Grignard reagent is any radical such as a lower alkyl or aralkyl radical which will react with the hydriodic acid to result in replacement of the ether group with the iodo radical. The resulting 5 H- 7 dibenzo[a,d]cycloheptene having an iodopropyl group at the S-carbon atom is the same as the one in method C, and, as in method C, may be converted to the primary amine of compounds ll. 7

ln method G. the reaction with the Grignard reagent may be carried out in the presence of a common solvent such as dry ether or tetrahydrofuran. the addition being slow to prevent a substantial temperature rise above room temperature. The usual procedures then are carried out. The primary amine of the end product of method G can be converted to a secondary amine by employing method B. 7

Still another method for producing the secondary amines of compounds ll involves a catalytic dibenzylation procedure. This may be represented as follows:

palladium ,lower alkyl Method H H CH CH N 2 2 lower alkyl The starting compound of method H will be recognized as the iodo derivative produced by method C and method G. It is gradually combined with the N-alkylbenzylamine to prevent a substantial temperature rise above room temperature, a solvent such as absolute al-- cohol being used. Heat to a refluxing temperature should be applied for from 15 to 60 minutes and the solvent distilled off. The selective debenzylation action of hydrogen in the presence of palladium is utilized to remove the benzyl moiety and produce the secondary amine of compound II. The alkyl radical of the N-alkylbenzylamine is selected to produce the radical R of compounds 11.

The following examples are illustrative of the many compounds contemplated by the invention and falling within the scope of the claim.

EXAMPLE 1 5-( 3-Aminopropylidene)-5H-dibenzo[ a,d lcycloheptene A. 5-Ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene 5l-l-dibenzo[a,d]cyclohepten-S-one (15.5 g., 0.075 mole) is added in portion to a solution of ethyl-magnesium bromide, prepared from 3.64 g. (0.15 mole) of magnesium and 16.4 g. of ethyl bromide in ether. After stirring for one hour at room temperature, the mixture is heated to refluxing for 15 minutes, then cooled, and the Grignard adduct is hydrolyzed by cautiously adding ammonium chloride solution. The crude 5-ethyl-5- hydroxy-Sl-l-dibenzo[a,d]cycloheptene is recovered from the ether layer in a yield of 16.78 g. (95%), m.p., 6365 (clearing at 70C.). After recrystallization from petroleum ether, hexane and finally isopropyl alcohol, an analytical sample melted at 6365C.

Analysis, Calcd. for C I-1 C, 86.40; H, 6.83.

Found: C, 86.31; H, 6.50.

B. -Ethylidene-5H-dibenzo[a,d]cycloheptene 5-Ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene (13.7 g., 0.058 mole) is dissolved in 80 ml. of acetyl chloride and the solution heated to refluxing for 90 minutes. The acetyl chloride is evaporated under reduced pressure and the residue dissolved in benzene. After washing with alkali followed by a water wash, the benzene is removed and the product distilled under reduced pressure. The desired S-ethylidene-Sl-l-dibenzo[a,d]cycloheptene is obtained as the fraction boiling at l30l35C. (0.02 mm.). It is crystallized on cooling. The compound was purified further by recrystallization from 95% alcohol.

C. 5-(2-Bromoethylidene )-5H-dibenzo[a,d]cycloheptene A mixture of S-ethylidene-SH-dibenzo[a,d]cycloheptene (10.9 g., 0.05 mole), N-bromosuccinimide (8.9 g., 0.05 mole), benzoyl peroxide mg.) and 150 ml. of carbon tetrachloride is stirred and heated to refluxing on the steam-bath for 4 hours. After cooling, the succinimide is separated by filtration and washed with carbon tetrachloride. The combined filtrate and washings are evaporated to dryness under reduced pressure. Crystallization of the residual solid from petroleum ether gave 5-(2-bromoethylidene)-5H-dibenzo[a,d]cycloheptene in a yield of 10.65 g. (72%), m.p.

87.589.5C. An analytical sample, after recrystallization from petroleum ether, melted at 90C. Analysis, Calcd. for C H Br: C, 68.70; H, 4.41; Br, 26.89.

Found: C, 68.51; H, 4.38; Br, 26.76.

D. 5-( 2-Cyanoethylidene)-5H-dibenzo[a,d ]cycloheptene A solution of 5-(2-bromoethy1idene)-5H-dibenzo[a,d]cycloheptene (7.5 g., 0.025 mole) in 75 ml. of acetone is treated with a solution of potassium cyanide. (5.0 g., 0.077 mole) in 15 ml. of water and the mixture heated to refluxing for 12 hours. The solution is evaporated to dryness under reduced pressure and the residue partitioned between ether and water. The ethereal layer is separated, washed with water, and dried over anhydrous sodium sulfate. Evaporation of the ether under reduced pressure gave an oily solid residue. Trituration with a mixture of petroleum ether ethr (3:1), 40 ml., afforded white crystals, m.p. -101C. The yield of 5-(2-cyanoethylidene)-5H-dibenzo[a,dlcycloheptene is 4.9 g. (81%). Repeated recrystallizations from isopropyl alcohol-water and from hexane gave an analytical sample melting at l03-l05C.

Analysis, Calcd. for C H N: C, 88.86; H, 5.38; N, 5.76.

Found: C, 88.95; H, 5.18; N, 5.74.

E. 5-( 3-Aminopropylidene )-5H-dibenzo[a,d]cycloheptene In a system protected by a drying tube and in which a nitrogen atmosphere is maintained, lithium aluminum hydride (380 mg., 0.01 mole) is suspended in 15 ml. of dry, peroxide-free tetrahydrofuran. The mixture is stirred and heated to refluxing for 4 hours. After cooling in an ice-bath, the mixture is stirred while a solution of 5-(2-cyanoethylidene)-5-H-dibenzo[a,d]cycloheptene (1.21 g., 0.005 mole) in 20 ml. of tetrahydrofuran is added dropwise over 20 minutes. The deep red solution is stirred for 1 hour in the cold and then hydrolyzed by the successive dropwise addition of water. 0.4 ml., 20% sodium hydroxide, 0.4 ml., and water, 1.0 ml. The granular precipitate is filtered and washed with absolute ether. The combined filtrate and washings are evaporated to dryness under reduced pressure. The residual yellow oily base is dissolved in absolute alcohol and treated with a solution of maleic acid in absolute alcohol. Dilution with ether precipitates the hydrogen maleate as white crystals, m.p. 17ll73C., dec. The yield of 5-(3-aminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrogen maleate is 0.45 g. (25%). Repeated crystallizations from mixtures of absolute alcohol-absolute ether gave an analytical sample melting at 176.5-l77.5C.,dec. Analysis, Calcd. forC H N. C H O C, 72.71; H, 5.83; N, 3.86.

Found: C, 72.79; H, 6.00; N, 3.79.

EXAMPLE 2 5-( 3-Ethylaminopropylidene )-5H-dibenzo[a,d]cycloheptene A. 5-(3-Acetamidopropylidene)-5l-l-dibenzo[a,d]cycloheptene 5-(3-Aminopropylidene)-5H-dibenzo[a,d]cycloheptene is dissolved in acetic anhydride and the solution is heated to refluxing for minutes. The solution is then cooled and poured into a large volume of water. The mixture is stirred until the excess acetic anhydride is hydrolyzed. The product is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.

cautiously, followed by sodium hydroxide solution. The ether layer is separated, washed with water and dried over sodium sulfate. The product is obtained by evaporation of the ether and purified by vacuum distillation.

EXAM PLE 3 5-( 3-Aminopropyl )-5H-dibenzo[a,d cycloheptene A. 5( 3-Ethoxypropyl )-5 -hydroxy-5H-dibenzo[a,d]cycloheptene The Grignard reagent is prepared from 12.55 g. (0.075 mole) of 3-ethoxypropyl bromide and 1.82 g. (0.075 mole) of magnesium in ether. The solution is cooled in an ice-bath and a solution of 5.15 g. (0.025 mole) of 5H-dibenzo[a,d]cycloheptemS-one in dry ether is added dropwise with stirring. The mixture is stirred at room temperature for 2 hours, then at reflux for 30 minutes. The Grignard adduct then is decomposed by pouring the reaction mixture into a mixture of ice and ammonium chloride solution. The ether layer is separated and the aqueous layer extracted further with ether. Evaporation of the ether gives the product an oily crystalline solid. Two recrystallizations from alcohol gave product, m.p., 129-l30C.

Analysis, Calcd. for C H O C, 81.60; H, 7.54. Found: C, 81.28; H, 7.50.

B. 5-( 3-lodopropyl)-5 H-dibenzo[a,d cycloheptene A solution of 9.25 g. (0.0314 mole). of 5-(3-ethoxypropyl )-5-hydroxy-dibenzo[a,d ]cycloheptene pared as above in 45 ml. of acetic anhydride is heated pre-,

on the steam-bath for 90 minutes then cooled to 659C.

A stream of nitrogen is passed through the solution while 30 ml. of hydroiodic acid (sp. gr., 1.5) is added in portions, keeping the temperature below 90C. The solution develops a dark brown iodine color during the addition. The solution is heated to 80C. for 30 minutes, then cooled and poured into ice-water. The brown oil that separates is extracted into benzene and the extract washed with water, dilute sodium thiosulfate solution and finally with water. Evaporation of the benzene gives the product 5-(3-iodopropyl)-5H-dibenzo-[a,d- ]cycloheptene as a yellow oil. A sample gives a precipitate with alcoholic silver nitrate solution.

C I g 5-( B-Phthalimidopropyl -5 H-dibenzo[a,d]cycloheptene i i 5(3-lodopropy1)-5H-dibenzo[a,d]cycloheptene, 1. 8 I

(0.005 mole), is dissolved'in 1O ml..of

dimethylformamide. The solution is stirred while 930" mg. (0.0051 mole) of potassium phthalimide is added. When the addition is complete, the. mixture isheatedto 90C. for 40 minutes, then cooled,diluted.with chloroform and poured into water. The chloroform layer is separated and the aqueous layer extracted further with chloroform. Evaporation of the chloroform gives the product as an oily crystalline solid. Several recrystallizations from isopropyl alcohol,

. i gave product, m.p. 125.5131.5C.

Found: C, 82.46; H, 5.60; N, 3.70. g D. 5-(3-Aminopropyl)-5H-dibenzo[a,d]cycloheptene 5-( 3Phthalimidopropyl )-5 H-dibenzo[a,d]cycloheptene, 2.15 g. (0.0054 mole), is dissolved in 50 ml. of hot ethanol. Hydrazine hydrate, 0.6 ml., is added 1 and the solution heated to refluxing for 2 hours; The solution then is cooled, acidified, and the precipitate of phthalhydrazide removed by filtration. Ethanol is dis-f tilled from the filtrate under reduced pressure and the. residue dissolved in 40 ml. of water. The filtered solu tion is evaporated by heating under reduced pressure to a volume of approximately 20 ml. Upon cooling, the

hydrochloride salt of 5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene is precipitated in a yield of 1.35 g.

(87.5%). After recrystallization from a mixture of etha-g no] and ether and from isopropyl alcohol, an analytical sample melted at 263265C., dec.

Analysis, Calcd. for C H N-HCI: C, 75.64;-H, 7.05;"

Found: C, 75.54; H, 6.77; N, 4.78.

EXAMPLE 4 I 5-( 3-n-Butylaminopropyl )-5H-dibenzo[a,d]cycloheptene A. r 5-( 3-Butyramidopropyl )-5H-dibenzo[a,d]cycloheptene A solution of 5-(3-aminopropyl)-5H-dibenzo[a,d]- i cycloheptene (0.75 g., 0.003 mole) in 5 ml. ofdry pyridine is treated with 0.7 ml. of butyric anhydride and then heated to refluxing for 30 minutes. Thecooled solution is poured into 50 ml.of water and the mixture allowed to stand at room temperature overnight. The oil is extracted into benzene and the benzene extract washed with water, 3N hydrochloric acid, and water.

Distillation ofthe benzene under reduced pressure gave an oily residue which solidified on standing. Trituration with .petroleumether afforded 5-(3-butyramidopropyl)-5H-dibenzo[a,d]cycloheptene as a white crystalline solid, mp 7680C., in a yield of 0.80 g.

B. k 5-( 3.-n-Butylaminopropyl)-5H-dibenzo[a,d]cycloheptene In a system protected by a drying tube and in which a nitrogen atmosphere is maintained, a solution of the Analysis Calcd. for C H O N: C, 82.30; H, 5.58;.N;

product from Step A. (0.80 g., 0.0075 mole) in 25 ml. of absolute ether is added dropwise to a stirred suspension of lithium aluminum hydride (0.19 g., 0.0025 mole) in ml. of absolute ether. After stirring at reflux for 1 hour, the mixture is cooled in ice and hydrolyzed by the successive dropwise addition of water, 0.2 ml., sodium hydroxide, 0.2 ml., and water, 0.6 ml. The granular precipitate is collected and washed thoroughly with ether. The combined ethereal filtrate and washings are washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual oily base is dissolved in absolute ether and treated with a solution of maleic acid (10% excess) in absolute alcohol. The 5-(3-n-butylaminopropyl)-5H-dibenzo[a,d- ]cyclopheptene hydrogen maleate is obtained by dilution of the solution with absolute ether as white needles, m.p. l02107C., in a yield of 0.65 g. (60%). Recrystallization from mixtures of isopropyl alcohol absolute ether and absolute alcohol absolute ether gives product, m.p. 107.5109C.

Analysis, Calcd. for C H N-C H O C, 74.08; H, 7.41; N, 3.32.

Found: C, 73.74; H, 7.38; N, 3.27.

EXAMPLE 5 5-( 3-Isopropylaminopropyl )-5 H-dibenzo[a,d]cycloheptene A suspension of platinum oxide (20 mg.) in 2 ml. of absolute alcohol is pre-reduced by shaking with hydrogen in a Hershberg apparatus. A solution of 5-(3- aminopropyl)-5H-dibenzo[a,d]cycloheptene (0.75 g., 0.003 mole) andacetone (0.5 ml.) in 5 ml. of absolute alcohol is added and the mixture shaken with hydrogen in a Hershberg apparatus until the hydrogen uptake is complete. Catalyst is filtered through a mat of diatomaceous earth and washed with absolute alcohol. The combined filtrate and washings are evaporated to dryness on the steam-bath under reduced pressure. The residual oily base is dissolved in absolute alcohol and treated with a solution of dry hydrogen chloride in absolute alcohol. The white crystalline 5-(3-isopropylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride is precipitated by addition of absolute ether in a yield of 0.80 g. (92%), m.p. 234-236C. The melting point was unchanged by a further recrystallization from a mixture of isopropyl alcohol and absolute ether.

Analysis, Calcd. for C H N-HCl: C, 76.92; H, 7.99; N, 4.27.

Found: C, 76.98; H, 7.78; N, 4.27.

EXAMPLE 6 5-( 3-Methylaminopropylidene )-5H-dibenzo[a,d ]cycloheptene A. 5-[ 3-(N-Cyano-N-methyl )aminopropylidene1-5H- dibenzo-[a,d]cycloheptene A solution of 23.06 g. (0.0834 mole) of 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene in 61 ml. of benzene is added dropwise to a stirred solution of 9.80 g. (0.0917 mole) of cyanogen bromide in 38 ml. of benzene. Some heat is evolved. The mixture is stirred for 3 hours at room temperature, and filtered to remove any precipitate which forms. The filtrate, together with a benzene wash of the precipitate, is evaporated to dryness on a steam-bath under reduced pressure to remove excess cyanogen bromide and solvent.

The residual crude cyanamide is dissolved in benzene, and the solution is washed with dilute hydrochloric acid to remove any unchanged amine, then with water. The benzene solution is then evaporated under reduced pressure leaving 5-[3-(N-cyano-N-methyl)aminopropylidene]-5H-dibenzo[a,d]-cycloheptene as a yellow oil weighing typically 19.6 g.

B. 5-( 3-Methylaminopropylidene )-5H-dibenzo[a,d ]cycloheptene The oily cyanamide (19.6 g.) prepared as in A above together with 500 ml. of glacial acetic acid, 330 ml. of

water, and 50 ml. of concentrated hydrochloric acid is heated under reflux for 16 hours, thereby effecting hydrolysis and decarboxylation and forming the product. The reaction mixture is concentrated to a small volume by heating under reduced pressure and the residue is dissolved in 250 ml. of water containing 1 ml. of concentrated hydrochloric acid. The aqueous solution is washed with benzene, and rendered alkaline by the addition of excess potassium carbonate. The free base thus liberated is extracted into ether and the ether solution dried over anhydrous potassium carbonate. Evaporation of the ether under reduced pressure on the steam-bath leaves a residue of 5-(3-methylaminopropylidene )-5H-dibenzo[a,d]cycloheptene, as an oil.

The free base may be converted to the oxalate by dissolution in warm absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After recrystallization from a mixture of methanol and ethyl acetate, the thus-formed hydrogen oxalate salt melts at about 202.5203.5C.

Analysis, Calcd. for C, H, N-C H O C, 71.78; H, 6.02; N, 3.99.

Found: C, 71.95; H, 6.00; N, 3.95.

Alternatively, the cyanamide can. be hydrolyzed under alkaline conditions as follows:

The cyanamide, obtained as described in Step A. (2.0 g., 0.007 mole) is mixed with a hot solution of 25 g. of potassium hydroxide in 38 ml. of absolute methanol. The mixture is heated to refluxing with stirring for 45 hours. The reaction mixture then is diluted with water and the yellow oil that separates is extracted into benzene. After washing with water and drying over sodium sulfate, the benzene is evaporated to give 1.75 g. of a yellow oily residue. The basic material is extracted into 1N hydrochloric acid and after separating the neutral material by extracting with ether, the basic material is recovered by making the aqueous layer basic and extracting with ether. Evaporation of the ether gives 1.46 g. of the base, 5-(3-methylaminopropylidene)-5H- dibenzo[a,d]-cycloheptene. Conversion to the oxalate is carried out as described above.

The hydrochloride salt may be formed directly from the crude free base or through the oxalate as follows: An aqueous solution of the oxalate salt is basified with lithium hydroxide and the free base extracted into benzene, Evaporation of the benzene leaves the base in substantially pure form. Treatment of the base with ethanolic hydrogen chloride and precipitation by the addition of ether gives the hydrochloride salt which, after recrystallization from a miture of ethanol and ether, melts at 180182C.

"143 ll) Analysis, Calcd. for C H N-HClz C, 76.61; H, 6.77; N, 4.70; Cl, 11.91;

Found: C, 76.93; H, 6.89; N, 4.65; Cl, 11.85.

EXAMPLE 7 5-(3-Methylaminopropylidene)-10,1 l-dihydro-Sl-ldibenzo-[a,d]cycloheptene Upon following the procedure given in Example 6 A., but employing an equivalent quantity of 5-(3-dimethylaminopropylidene)-10,1 l-dihydro-Sl-l-dibenzo[a,d]cycloheptene in place of 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene, the corresponding cyanamide is obtained. Upon hydrolysis, according to the procedure of Example 6 13., there is obtained 5-(3-methylaminopropylidene)-10,1l-dihydro 5h-dibenzola,d]cycloheptene. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6 B. After recrystallization from a mixture of alcohol and ether, the hydrochloride salt melts at about 215.7 216.7C.

Analysis, Calcd. for C H N-HCI: C, 76.10; H, 7.40; N,4.67.

Found: C, 76.08; H, 7.30; N, 4.54.

EXAMPLE 8 5-( 3-Methylaminopropyl)-5 l-l-dibenzo[ a,d lcycloheptene Upon following the procedure given in Example 6 A,

but employing an equivalent quantity of 5-(3dimethylaminopropyl)-5l-l-dibenzo{a,d]cycloheptene in place of 5-(3-dimethyl aminopropylidene)-5H-dibenzo[a,d]-cycloheptene, the corresponding cyanamide is obtained. Upon hydrolysis, according to the procedure of Example 6 B., there is obtained 5-(3-methylamino propyl)-5l-1-dibenzo[a,d]cycloheptene. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6 B. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride salt melts at l66.5167.5C. (uncorrected).

Analysis. Calcd. for C H N-HCl: C, 76.11; H, 7.40; N, 4.67.

Found: C, 76.14; H, 7.30; N, 4.64.

EXAMPLE 9 5 3-Dimethylaminopropyl )-5 l-l-dibenzo[a,d cycloheptene hydrochloride A. 3-Dimethylaminopropylmagnesium chloride Magnesium turnings (1.08 g., 0.0442 g. atom) are placed in a 200 ml. 3-necked flask equipped with a stirrer, a dropping funnel and a reflux condenser carrying a drying tube. An atmosphere of drynitrogen is maintained in the apparatus throughout the reaction. A crystal of iodine is added followed by 10 ml. of dry tetrahydrofuran. A 3 ml. portion of 3-dimethylaminopropylmagnesium chloride solution from a previous experiment is added and the mixture heated to refluxing in the steam-bath. A solution of 3-dimethylaminopropyl chloride (5.37 g., 0.0442 mole) in 35 ml. of dry tetrahydrofuran is added dropwise, refluxing being maintained by the application of heat when necessary. When the addition is complete, the mixture is refluxed for 2 hours when almost all of the magnesium is dissolved.

Instead of using 3-dimethylaminopropylmagnesiu'm chloride to initiate the reaction, ethyl bromide can be employed in a quantity of 0.05 mole per mole of mag I nesium.

B. 5-(3-Dimethylaminopropyl)-51-i-dibenzo[a,d]cycloheptene hydrochloride The Grignard solution prepared in Step A. is cooled to room temperature and stirred while a solution of 5.05 g. (0.0221 mole) of 5-chloro-5l-l-dibenzo[a,d]-,

cycloheptene in 25 ml. of dry tetrahydrofuran is added dropwise, external cooling being applied as required to maintain the temperature close to room temperature. When the addition is complete, the mixture is heated to refluxing for 15 minutes. The bulk of the tetrahydrofui ran then is distilled under reduced pressure, keeping.

the water-bath temperature at 5060C. The syrupy mixture is disclosed in ml. of benzene and water, 15 ml'., is added dropwise with stirring. The benzene layer is decanted from. the gelatinous precipitate which then is re-extracted with three 20 ml. portions of boiling, benzene. The combined benzene extracts are washed Q with water and extracted with three 15 ml. portions of 3N hydrochloric acid. The acid extract is made basic with sodium hydroxide and the yellow oily base that separates is extracted into hexane. After washing the 1 combined extracts with water, the hexane is evaporated" and the product obtained as a yellow oil in a yield of 4.61 g. The base is converted to the hydrochloride by dissolving it in a mixture of 15 ml. of absolute alcohol and 15 ml. of absolute ether and adding 1.8 ml. of a 10.28 N, solution of dry hydrogen chloride in absolute alcohol. The solution then is diluted to incipient crystallization by the addition of 25 ml. of absolute ether. The yield of 5-(3-dimethylaminopropyl) 5H-dibenzo[a,d]cycloheptene hydrochloride, m.p. 186190C. is 4.17 g. Recrystallization from mixtures of absolute alcohol and absolute ether gives the product, m.p.'

Analysis, Calcd. for C H- Ni-iclz C, 76.53; H, 7.71; Q i I Found: C, 76.23; H, 7.83; N, 4.45.

EXAMPLE 10 10,11-Dihydro-5-(3-methylaminopropyl)-5H-dibenzo[a,d]-cycloheptene A 10,1 1-Dihydro-5-(3-dimethylaminopropyl)-5H-' dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 6A. The cyanamide (5.03 g.) together with 60 0 ml. of glacial acetic acid, 40 ml. of water and 8 ml. of

concentrated hydrochloric acid is heated to refluxing for 16 hours. The reaction mixture is evaporated to dryness by heating under reduced pressure. Crystallization of the residual solid from isopropyl alcohol gives EXAMPLE 11 3-Chloro- 10,1 l-dihydro--( 3-methylaminopropyl)- 5H-dibenzo-[a,d]cycloheptene 3-Chloro-10,1 1-dihydro-5-( 3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 6 A. Upon hydrolysis, according to the procedure of Example 6 B., there is obtained 3- chlorol 0,1 l-dihydro-5-(3-methylaminopropyl)-5H- dibenzo[a,d]cycloheptene. This may be converted to its hydrochloric salt directly by treatment with ethanolic hydrogen chloride as described in Example 6 B. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride, salt melts at l92.5l93.5C., dec.

Analysis, Calcd. for C, H NCl'HCl: C, 67.85; H, 6.89; N, 4.17.

Found: C, 68.09; H, 6.94; N, 4.13.

The starting 3-chloro-l0,1l-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene used in this example may be prepared by following Steps A. and B. of the above Example 9, employing 3,5- dichloro-l0,1 l-dihydro-5H-dibenzo[a,d]cycloheptene as the starting compound.

EXAMPLE 12 5-( 3Aminopropyl)-5H-dibenzo[a,d]cycloheptene A. 5-(3-Ethoxypropyl)-5H-dibenzo[a,d]cycloheptene the Grignard reagent is prepared from 6.44 g. (0.0386 mole) of 3-ethoxypropyl bromide and 940 mg. (0.0386 g. atom) of magnesium in ether. A solution of 5.67 g. (0.025 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in a mixture of dry ether and tetrahydrofuran is added dropwise with stirring. The mixture is stirred at room temperature for 1 hour. The Grignard adduct then is decomposed by pouring the reaction mixture into a mixture of ice and ammonium chloride solution. The ether layer is separated, the aqueous layer extracted further with ether. Evaporation of the ether and distillation of the residue under reduced pressure gives the product as a yellow oil, b.p. l45148C. (0.1 mm.)

Analysis, Calcd. for C H Oz C, 86.28; H, 7.97.

Found: C, 86.84; H, 7.97.

B. 5-(3-Iodopropyl)-5H-dibenzo[a,d]cycloheptene This product is obtained by following the precedure of Example 3 B., but starting with 5-(3-ethoxypropyl)- 5H-dibenzo[a,d]cycloheptene. To obtain as the end product the compound of the title, the remaining procedure of Example 3 is followed.

EXAMPLE l3 3-Chloro-5-( 3aminopropyl )-5 H-dibenzo[a,d]cycloheptene 3-Chloro-5( 3-ethoxypropyl)-5 H-dibenzo[a,d ]cycloheptene 3,5-Dichloro-5H-dibenzo[a,d]cycloheptene, dissolved in absolute ether, is added dropwise with stirring to a solution containing one equivalent of 3-ethoxypropylmagnesium bromide in ether. The mixture is stirred at room temperature for 1 hour, then at reflux for 2 hours. The mixture then is cooled, treated with 22 dilute hydrochloric acid and the ether separated, washed with water and dried. The product is isolated by evaporation of the ether.

B. 3-Chloro 5 3-iodopropyl)-5H-dibenzo[a,d]cycloheptene 3-Chloro-5-( 3-ethoxypropyl )-5H-dibenzo[a,d

cycloheptene (0.03 mole) is dissolved in 45 ml. of

acetic anhydride. The solution is heated to C. and nitrogen is passed through while 30 ml. of hydriodic acid (sp. gr., 1.5) is added gradually, keeping the temperature below 90C. The solution is heated to approximately C. for 30 minutes, then cooled and poured into ice-water. The product is extracted into ether, the extract washed with dilute sodium thiosulfate solution, followed by dilute sodium bicarbonate solution and finally with water. The product is isolated by evaporation of the ether.

C. 3-Chloro-S-( 3-phthalimidopropyl )-5H-dibenzo[a,d]-

cycloheptene 3-Chloro-5-(3-iodopropyl)-5H-dibenzo[a,d] cycloheptene is converted to 3-chloro-5-(3- phthalimidopropyl)-5H-dibenzo[a,d]cycloheptene by following the procedure of Example 3, Step C.

D. 3-Chloro-5-( 3-aminopropyl )-5H-dibenzo[ a,d]cycloheptene 3-Chloro-5-(3-phthalimidopropyl)-5H-dibenzo-[a,d- ]cycloheptene is converted to 3-chloro-5(3-aminopropyl)5H-dibenzo[a,d]cycloheptene by following the procedure of Example 3, Step. D.

EXAMPLE l4 3-Chloro-5-( 3-ethylaminopropyl )-5 H-dibenzo[ a,d]cycloheptene A. 3-Chloro-5-( 3-acetamidopropyl)-5 H-dibenzo[ a,d ]cycloheptene 3-Chloro5-(3acetamidopropyl)-5H-dibenzo[a,d]- cycloheptene is dissolved in absolute ether. The solution is added dropwise to a stirred solution of lithium aluminum hydride in ether, containing 1.25 molar equivalents of the hydride. The mixture is stirred for 2 hours at room temperature, then for 1 5 hours at reflux. The mixture then is cooled and stirred while water is added cautiously followed by sodium hydroxide solution. The ether layer is separated, washed with water and dried over sodium sulfate. The product is obtained by evaporation of the ether and purified by vacuum distillation.

EXAMPLE 15 5-[3-(N-BenzyI-N-ethylamino)-propyl]-5H-dibenzo[a,d]cycloheptene is dissolved in absolute alcohol and hydrogenated over palladium on alumina catalyst at 4060C. The catalyst is separated and the product isolated by evaporating the solvent.

EXAMPLE l6 5-( 3-Ethylaminopropyl )-5 I-I-dibenzo[ a,d]cycloheptene 5 3-Acetamidopropyl )-5 I-I-dibenzo[a,d]cycloheptene A solution of 5-(3-aminopropyl)-5H-dibenzo[a,d]- cycloheptene (0.75 g., 0.003 mole) in 5 ml. of dry pyridine is treated with 1 ml. of acetic anhydride and then heated to refluxing for 30 minutes. The cooled solution is poured into I ml. of water and the oil extracted into benzene. The benzene extract is washed with water, 3N hydrochloric acid, water, and evaporated to dryness under reduced pressure. The 5-(3-acetamidopropyl)-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oily residue weighing 0.87 g.

B. 5-( 3-Ethylaminopropyl )-5I-I-dibenzo[a,d]cycloheptene In a system protected by a drying tube and in which a nitrogen atmosphere is maintained, a solution of the product from Step A. (0.87 g., 0.003 mole) in 25 ml. of

absolute ether is added dropwiseover a period of 30 minutes to a stirred solution of lithium aluminum hydride (0.25 g., 0.0066 mole) in 15 ml. of absolute ether. After stirring at reflux for 6 hours, the mixture is allowed to stand at room temperature overnight. The mixture is cooled in ice and stirred while water, 0.25

ml., 20% sodium hydroxide, 0.25 ml., and water, 0.75 ml. are added cautiously dropwise in succession. The granular precipitate is collected and washed thoroughly with ether. The combined ethereal filtrate and washings are washed with water and dried over anhydrous sodium sulfate. Ether is evaporated under reduced pressure to obtain the oily base. The hydrochloride is.v

prepared by treating a solution of the base in absolute alcohol absolute ether with a solution of dry hydrogen i chloride in absolute alcohol. The white crystalline .5-(3- ethylaminopropyl)-5H-dibenzo-[a,d]cycloheptene hydrochloride is obtained by dilution of the solution with,

absolute ether in a yield of 0.50 g. (53%), mp.

224.5-226.5C.', dec. Repeated recrystallizations from absolute alcohol absolute ether and isopropyl alcohol absolute ether mixtures raised the 227.5228.5C., dec.

Analysis, Calcd. for C H NHCI: C, 76.53;]1, 7.71; N,4.46.

Found: C, 76.28; H, 7.68; N, 4.42.

EXAMPLE l7 3-Chloro-5-(3-methylaminopropyl)-5H-dibenzo[a,d{ I

]cycloheptene A. 3-Chloro-5-( 3-dimethylaminopropylt)-5H-diben zo[a,d]-cycloheptene I 3-Dimethylaminopropylmagnesium chlorideiis pre- I pared from magnesium turnings (1.22 g., 0051' g. atom) and 3-dimethylaminopropyl chloride (6.2 g.,

0.051 mole) in 25 ml. of tetrahydrofuran following the,

method of Example 9, Step A. In a nitrogen atmo sphere, a solution of 3,S-dichloro-SH-dibenzo[a,d]cycloheptene (6.65 g., 0.0255 mole) in 40 ml. of tetrahydrofuran is added dropwise to the stirred solution of the Grignard reagent while cooling in an icebath. The miX-,

ture is allowed to come to room temperature and stirred for 2 hours. The bulk of the solvent then in distilled below 50C.under reduced pressure. The residue 7 is dissolved in 50 ml. of benzene and water, 20 ml.; is. added dropwise with stirring and cooling. The benzene layer is decanted from the gelatinous precipitate which, L

then is re-extracted with three 20 ml. portions of boiling benzene. The combined benzene extracts: vare washed with water and extracted with three 50 ml. por-' tions of 1N hydrochloric acid. The acid extract is made basic with sodium hydroxide and the oily base that separates is extracted into hexane. After washing the combined extracts with water and drying over anhydrous I sodium sulfate, the hexane is evaporated and the product obtained as a yellow oil in a yield of 6.13 'g. The base is converted to the hydrogen maleate by dissolving it in 25 ml. of isopropyl alcohol and adding a solution of 2.5 g. of maleic acid in ml. of isopropyl alcohol. Di-

' I lution to incipient crystallization with 50 mI/of absoflute ether precipitates 3chloro-5'(3-dimethylaminopropyl)-5II-dibenzo[a,d]cycloheptene hydrogen male ate, m.p. l44l49C. in a yield of 5.9 g. Recrystallization from mixtures of absolute alcohol absolute ether 6 and isopropyl alcohol absolute ether gives theprod- Analysis, Calcd. for C H NCl'C l-I O i C, 67.37; H,

Found: C, 67.54; H, 6.22; N, 3.21.

3-Chloro-5-(3-N-cyano-N-methylaminopropyl)-5I-I- I dibenzo-[a,d]cycloheptene In a system protected by a drying tube and in which i a nitrogen atmosphere is maintained, a solution of 3- chloro-5-(3-dirnethylaminopropyl)-5I-I-dibenzo[a,d- ]cycloheptene (0.78 g., 0.0025 mole) in 5 ml. of benzone is added dropwise to a stirred solution of cyanogen bromide, 0.7 ml. ofa 4.25M solution in benzene, in 4.3 m1. of benzene. Stirring is continued for 1% hours and the mixture then allowed to stand at room temperature overnight. Solvent and excess cyanogen bromide are evaporated under reduced pressure and the residue dissolved in benzene. The solution is washed with dilute hydrochloric acid, then with water, and evaporated to dryness under reduced pressure. The 3-chloro-5-(3-N- cyano-N-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oily residue weighing 0.77 g. (95.5%).

C. 3-Chloro-5-( 3-methylaminopropyl)-5H-dibenzo[a,d]- cycloheptene The oily cyanamide (0.77 g.) prepared as in B. above, is hydrolyzed according to the procedure of Example 6 B. There methylaminopropyl)-5H-dibenzo[a,d]cycloheptene as an oil weighing 0.60 g. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6 B. After.

recrystallization from mixtures of isopropyl alcohol absolute ether and absolute methanol acetone, the' white crystalline hydrochloride melts at 193195C., dec.

Analysis, Calcd. for C H Ncl-HClz C, 68.26; H, 6.33; N, 4.19.

Found: C, 67.89; H, 6.39; N, 4.10.

EXAMPLE 18 3-Dimethylsulfamoyl-5-( 3-methy1aminopropy1)-5H- dibenzo-[a,d]cycloheptene A. 3-Bromo-7-fluorosulfonyl-10,1 1 -dihydro-5 H-dibenzo[a,d]-cyclohepten-5-one Fluorosulfonic acid, 100 ml., is placed in a 300 ml. 3-necked round bottom flask equipped with polyethylene inlet tube and polyethylene exit tube with drying tube half-filled with anhydrous sodium fluoride. A nitrogen atmosphere is maintained throughout the reaction. With stirring, 17.0 g. (0.059 mole) of 3-bromo- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is added in portions over 20 minutes. After stirring another minutes, the dark green solution is heated on the steam-bath for 6% hours. The mixture then is cooled to room temperature, poured cautiously with stirring into 1.5 kg. of crushed ice, and allowed to stand overnight at room temperature. The brown solid is collected, washed with water, dried in a vacuum desiccator over sodium hydroxide, and then extracted in a Sohxlet extractor with 700 ml. of boiling cyclohexane for 16 hours. On cooling, the cyclohexane extract deposits 11.65 g. (53%) of 3-bromo-7-fluorosulfonyl- 10,1 1-dihydro-5H-dibenzo[a,d]-cyc1ohepten-5-one as dark yellow flakes, m.p. 148l 5 1C. Recrystallizations from ether and cyclohexane give an analytical sample, m.p. 150l52C.

Analysis, Calcd. for C H O FBrS: C, 48.79; H, 2.73; S, 8.69.

Found: C, 48.78; H, 2.83; S, 8.87.

B. 3-Bromo-7-dimethylsulfamoyll 0,1 1 -dihydro-5H- dibenzo-[a,d ]cyclohepten-S-one 3-Bromo-7-fluorosulfonyl-10,1 l-dihydro-SH-dibenis obtained 3-chloro-5-(3-' z0[a,d]cyclohepten-5-one (2.5 g., 0.00677 mole) together with 30 ml. of 25% aqueous dimethylamine and 30 ml. of p-dioxane is heated to refluxing for 3 hours. The brown solution is evaporated to dryness under reduced pressure and the residue partitioned between benzene and water. After washing with water, the benzene layer is evaporated to dryness under reduced pressure, leaving 3-bromo-7-dimethylsulfamoyl-10,l 1- dihydro-5H-dibenzo[a,d]-cyclohepten-5-one as a tan solid, m.p. 142145C., in a yield of 2.1 g. (80%). An analytical sample melts at l46148C. after crystallizations from mixtures of benzene and hexane and from methanol.

Analysis, Calcd. for C -,H, O NBrS: C, 51.78; H, 4.09; N, 3.55.

Found: C, 51.71; H, 4.12; N, 3.53;

C. 3-Dimethylsulfamoyl-10,1 l-dihydro-5H-dibenzo[a,d cyclohepten-S-one 3-Bromo-7-dimethylsulfamoyl-10,1 l-dihydro-SH- dibenzo[a,d]cyclohepten-S-one, 8.0 g. (0.0203 mole), is dissolved in a mixture of 100 ml. of absolute ethanol, ml. of dimethylformamide, and 5 m1. of triethylamine. The solution is hydrogenated at atmospheric pressure and in the presence of 600 mg. of 10% palladium on charcoal catalyst until hydrogen uptake is complete. Catalyst is removed by filtration and washed with absolute ethanol. The filtrate is evaporated to dryness under 5 reduced pressure and the residue triturated with benzene. The insoluble triethylamine hydrobromide is filtered and the benzene filtrate evaporated to dryness under reduced pressure. Crystallization of the residual white solid from absolute ethanol affords 6.1 g. (97%) of 3-dimethylsulfamoyl-l0,l l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one, m.p. l22124C. The melting point is unchanged after crystallization from absolute ethanol.

Analysis, Calcd. for C H O NS: C, 64.74; H, 5.44; N, 4.44.

Found: C, 64.20; H, 5.47; N, 4.16.

D. 3-Dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten- 5-one A mixture of 3-dimethylsulfamoyl-10,l l-dihydro- 5H-dibenzo[a,d]cyclohepten-S-one (6.1 g., 0.0194 mole), N-bromosuccinimide (3.6 g., 0.029 mole), benzoyl peroxide (50 mg.) and 50 m1. of benzene is stirred and heated to refluxing for 3 hours. The precipitated succinimide is filtered and washed with warm benzene. After washing with 5% aqueous sodium hydroxide and then with water, the benzene filtrate is evaporated to dryness under reduced pressure. The residual oily solid is suspended in ml. of triethylamine and the mixture stirred at reflux for 16 hours. Triethylamine is evaporated under reduced pressure and the residual solid .partitioned between benzene and water. The benzene layer is separated, washed with 3N hydrochloric acid and then with water, and evaporated to dryness under reduced pressure. Crystallization of the residual solid from ethanol gives 2.83 g. (46.5%) of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-S-one, m.p. l29.5135.5C. An analytical sample melts at l38.5139.5C. after repeated crystallizations from 95% ethanol.

Analysis, Calcd. for C H O NS: C, 65.16; H, 4.83; N, 4.17.

Found: C, 64.88; H, 4.85; N, 4.11.

E. 3-Dimethylsulfamoyl-5H-dibenzo[a,d ]cyclohepten-- 3-Dimethylsulfamoyl5H-dibenzo[a,d]cyclohepten- 5-one (6.9 g., 0.022 mole) and 100 ml. of absolute methanol are stirred and heated to refluxing. A solution of 1.6 g. (0.0296 mole) of potassium borohydride in 12 ml. of water containing 1 pellet of potassium hydroxide is added dropwise at a rate such that reflux is maintained without external heating. After another 1 /2 hours at reflux, the solution is evaporated to dryness under reduced pressure. The residual which solid is suspended in water, collected, andcrystallized from 95% ethano. The yield of 3-dimethylsulfamoyl-5H-dibenzo- [a,d]cyclohepten-5-ol is 6.05 g. (87%), m.p. l50152C. The melting point is unchanged by further recrystallization.

Analysis, Calcd. for C,-,H, O NS: C. 64.74; H, 5.44; N, 4.44.

Found: C, 64.22;H, 5.44; N, 4.40.

F. 5-Chloro-B-dimethylsulfamoyl-S H-dibenzo[a,d]cycloheptene A solution of 1.0 g. (0.00317 mole) of 3-dimethylsulfamoyl-SH-dibenzola,d]cyclohepten-5-ol in a mixture of 2 ml. of dry dioxanc and 2 ml. of absolute ether is cooled in ice and saturated with dry hydrogen chloride. The mixture is allowed to stand at room temperature for 5 hours and then is refrigerated overnight. The white crystalline product is collected, washed with petroleum ether, and dried in a vacuum desiccator over calcium chloride. The yield of 5-chloro-3-dimethylsulfamoyl-5H-dibenzo-[a,d}cycloheptene is 600 mg, m.p. l39.5l43.5C. Dilution of the mother liquor with petroleum ether gives a second crop which is recrystallized from a mixture of ether and petroleum ether affording 250 mg., m.p. 138.5l42.5C.

Analysis, Calcd. for C H O NCIS: C, 61.16; H, 4.83; N, 4.20.

Found: C, 61.15; H, 4.57; N, 4.11.

G. 3-Dimethylsulfamoyl-5-( 3-dimethylaminopropyl )-5 H- dibenzo{ a,d ]cycloheptene By replacing the 3,5-dichloro5H-dibenzo[a,d]- cycloheptene used in Example 17, Step A., with an equimolecular amount of 5-chloro-3-(dimethylsulfamoyl)-5H-dibenzo[a,d]eycloheptene and following substantially the same procedure described in Example 17, Step A., there is obtained 3-dimethylsulfamoyl-5- (3-dimethylaminopropyl)-5H-dibenzo[a,d]eycloheptene. The yield of yellow oily base is 50%.

H. 3-Dimethylsulfamoyl-5-( 3-methylaminopropyl )-5 H- dibenzo[a,d ]cycloheptene 3-Dimethylsulfam0yl5-(3-dimethylaminopropyl)- 5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 17, Step B. The cyanamide (0.28 g., 0.00071 mole) together with 2.8 ml. of glacial acetic acid, 2.0 ml. of water and 0.4 ml. of concentrated hydrochloric acid is heated to refluxing for 29 hours. The reaction mixture is evaporated to dryness under reduced pres sure and the residue is dissolved in water. The aqueous solution is made alkaline with sodium hydroxide and the oily base that separates is extracted into ether. The

washed and dried ether extract is evaporated under reduced pressure, methylaminopropyl)-5H-dibenzo[a,d]cycloheptene as an oil weighing 170 mg. The base may be convertedto the hydrogen oxalate salt by dissolution in absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After repeated recrystallizations fromabsolute ethanol and from isopropyl alcohol, the hydrogen oxalate melts at 135.5-I35.5C., dec.

Analysis, Calcd. for C H O N S-C H O C. 59.98;

Found: C, 60.00;H, 6.42; N, 6.09.

EXAMPLE 19 3-Chloro-5-( 3-methylaminopropylidine )-5 H-diben-i zo[a,d]-cyeloheptene hydrochloride (a and B-isomers) dibenzo[a,d]cycloheptene in 4 ml. of dry benzene is added dropwise to a solution of cyanogen bromide (0.915 g., 000,86 mole) in 3 ml. of dry benzene, while stirring and maintaining a slow stream of nitrogen. through the apparatus. A solid separates and 4 ml. of

benzene is added to facilitate stirring which is continued for 4 hours. The solid is removed by filtration.

through a sintercd glass funnel and washed with ben:

zene. Solvent and excess cyanogen bromide are evapo rated from the combined filtrate and washings under reduced pressure. The residue is dissolved in 30 mlaof benzene and the solution washed with 1N hydrochloric I acid and then with water. Evaporation of the benzene 1 under reduced pressure gives 3chloro-5-[3(N-cyano-.

N-methyl)-aminopropylidene]-5 H-clibenzo[a,d]c'ycloheptene as a white solid, m.p. 115-118.5C., in a. yield of 1.9 g. (83%). An analytical sample melts at 1 l7.5l18.5C. after recrystallization from cyclohexane.

Analysis, Calcd. for C H N CI: C, 74.89; H, 5.34; N, 8.74. 4

Found: C, 74.71; H, 5.23; N, 8.61.

3-Chloro-5-( 3-methylaminopropylidene)-5H-diben' zo[a,d]-cycloheptene hydrochloride (a and B-isomers) 3-Chloro-5-[3-(N-cyano-N-methyl)aminopropylidene]-5H-dibenzo[a,d]cycloheptene 1 (1.5 I g., 0.00467 mole) and a solution of potassiumhydroxide (16.7 g., 0.254 mole) in 25 ml. of absolute methanol 5 was stirred and heated to refluxing for 48 hours. The j cooled mixture is diluted with ml. of water and the oil that separates is extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves an oil which then is dissolved in 70 ml. of absolute ethenThe ethereal solution is filtered from a trace of flocculent precipitate and the ether is evaporated under reduced pressure. The. 3--

chloro-5-( methylaminopropylidene )-5H-dibenzo[a,d-

]cycloheptene is obtained as a yellow oily residueweighing 1.19 g. The product is converted to the hydrochloride by treating a solution of the base in 9 ml. ofabsolute ethanol with 1.17 ml. of 4.13N hydrogen chlo ride in absolute ethanol. The 3-chloro5-(3- methylaminopropylidene )-5 H-dibenzo[a,d]cyclohepleaving 3-dimethylsulfamoyl-5-( 3- V tene hydrochloride is separated into the aand B-forms by fractional precipitation from the ethanolic solution with absolute ether. The a-form melts at 263265C., dec. after repeated recrystallizations from a mixture of absolute ethanol and absolute ether.

Analysis, Calcd. for C l-l NCl-HCl: C, 68.68; H, 5.76; N, 4.22.

Found: C, 68.60; H, 5.60; N, 4.16. The fi-form melts at 187l 89C. (cloudy melt clear at 191C.) after repeated recrystallization from ethanol ether and isopropyl alcohol ether mixtures.

Analysis, Calcd. for C H NCl-HCl: C, 68.68; H, 5.76; N, 4.22.

Found: C, 68.00; H, 5.83; N, 3.91.

EXAMPLE 20 l-Bromo-5-( 3-methylaminopropylidene )-5 H-dibenzo[a,dl-cycloheptene A. l0-Bromo-5-( 3-dimethylaminopropyl)-5-hydroxy-5l-ldibenzo a,d ]cycloheptene 3-Dimethylaminopropylmagnesium chloride is prepared from 3.4 g. (0.14 g. atom) of magnesium and 17.0 g. (0.14 mole) of B-dimethylaminopropyl chloride in 50 m1. of dry tetrahydrofuran, following the method of Example 9, Step A. A solution of 20.0 g. (0.07 mole) of -bromo-SH-dibenzo[a,d]cycloheptene-5-one in 40 ml. of tetrahydrofuran is added dropwise to the Grignard solution while cooling in an ice-bath and stirring over a period of 30 minutes. The mixture is allowed to warm up to room temperature and stirred for 2 hours. The bulk of the solvent then is distilled below 50C. under reduced pressure, the residue dissolved in 50 ml. of benzene and the Grignard adduct hydrolyzed by the addition of 25 ml. of water to the solution while stirring and cooling. The benzene solution is separated from the magnesium slurry by decantation and the slurry extracted with additional portions of benzene. After washing with water, the benzene is distilled from the combined extracts to give 25.67 g. of a yellow oily residue. The residue is dissolved by warming in 350 ml. of 0.5N citric acid solution and the solution backextracted with benzene. The acid extract then is rendered alkaline with sodium hydroxide and the base extracted into methylene chloride. After washing with water, the solvent is evaporated and the residue crystallized from a mixture of cyclohexane and hexane. The yield of white crystalline product, m.p. ll8-l 19.5C. is 20 g. Recrystallization from hexane raises the m.p. to ll8.5-l20C.

Analysis, Calcd. for C H BrNO: C, 64.54; H, 5.96; N, 3.76.

Found: C, 64.26; H, 5.93; N, 3.76.

B. l0-Bromo-5-(3-dimethylaminopropylidene )-5l-l-dibenzo[a,d ]-cycloheptene l0-Bromo-5-(3-dimethylaminopropyl)-5-hydroxy- 5H-dibenzo[a,d]cycloheptene (14.75 g., 0.0396 mole) is dissolved in 100 ml. of trifluoroacetic acid. Trifluoroacetic anhydride, 50 ml., is added and the solution heated to refluxing with stirringfor 1% hours. The excess trifluoroacetic anhydride and the trifluoroacetic acid are distilled, the residue suspended in water and 30 the mixture rendered alkaline with sodium hydroxide solution. The base is extracted into ether. After washing the extract with water, the ether is distilled, leaving the oily product as the residue in a yield of 13.75 g.

C. l0-Bromo-5-[ 3-( N-cyano-N-methyl)-aminopropylidene1-5 H-dibenzo[a,d]cycloheptene l0-Bromo-5-(3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene (2.83 g., 0.008 mole) in 2 ml. of dry benzene is added dropwise to a solution of 1.02 g. (0.0096 mole) of cyanogen bromide in 4 ml. of benzene while stirring and maintaining the temperature at 2530C. A slow stream of nitrogen is swept through the apparatus throughout the addition. After the addition is complete the mixture is stirred for 4 hours, then allowed to stand 15 hours at room temperature. The solvent is distilled under reduced pressure. The residue is taken up in methylene chloride and taken to dryness again. The residue then is dissolved in methylene chloride and the solution extracted with 1N hydrochloric acid. After washing with water, the methylene chloride solution is dried over sodium sulfate and evaporated to give 2.15 g. of the product as an oily residue.

D. 10-Bromo-5-( 3-methylaminopropylidene )-5H-dibenzo[a,d ]-cycloheptene l0-Bromo-5-[3-(N-cyano-N-methyl)-aminopropylidene]-5H-dibenzo[a,d]cycloheptene (2.0 g.. 0.00548 mole) is dissolved in 40 ml. of glacial acetic acid. Water, 27 ml., and concentrated hydrochloric acid, 4 ml., are added and the mixture is heated to refluxing with stirring for 17 hours. The bulk of the solvent is distilled under reduced pressure and the residue is dissolved in 65 m1. of water and the solution extracted with benzene. The aqueous layer is rendered alkaline with sodium hydroxide and the product is extracted into benzene. After washing with water, the benzene is distilled, leaving the mixed geometric isomers of 10-bromo-5-(3-methylaminopropylidene)-5H- dibenzo[a,d]cycloheptene as a yellow oily residue in a yield of 1.86 g.

E. l0-Bromo-5 (3-methylaminopropylidene)-5H-dibenzo[a,d]-cycloheptene hydrogen maleate (oz-isomer) A 1.65 g. (0.00485 mole) portion of the product of Step D. is dissolved in 15 ml. of absolute alcohol. A solution of maleic acid (0.620 g.. 0.00533 mole) in absolute alcohol (4 ml.) is added and the solution diluted with absolute ether to incipient cloudiness. A first crop of crystals weighing 0.55 g. is collected. This material sintered at 153.5C; and melted at 159C. A second crop of product weighing 0.25 g., m.p. l5l.5l55.5C., is obtained from the mother liquors. The combined products are recrystallized three times from methanol ether mixtures to give material with a constant m.p. of l66167.5C.

Analysis, Calcd. for C H, BrN'C H.,O C, 60.53; H, 4.86; N, 3.07.

Found: C, 60.75; H, 4.95; N, 2.90.

F. l0-Brorno-5-(3-methylaminopropylidene)-5H-dibenzo[a,d1-cycloheptene hydrogen oxalate (B-isomer) The mother liquors from another experiment such as E. are concentrated and amorphous hydrogen maleate of the B-isomer is converted to the base. The base, 10.8 g., is dissolved in 20 ml. of benzene and 10 ml. of the solution applied to each of two chromatography columns constructed of polyethylene tubing, 2 cm. in diameter and packed with 60 g. of alumina (Merck, reagent) activated in situ by means of acetone. Each column is developed by passing 100 ml. of chloroform through it. The columns then are slit longitudinally. A zone is visible approximately /3 of the distance from the top of the absorbent. The section of the column below this zone is removed and eluted with boiling methanol. After separating the solid, the methanol is distilled, leaving 1.66 g. of a yellow oily residue. A 0.49 g. (0.00144 mole) portion of this base is dissolved in 10 ml. of absolute ethanol and treated with a solution of of 0.142 g. (0.00158 mole) of oxalic acid in 5 ml. of absolute methanol. The hydrogen oxalate salt of the product separates as a pale yellow solid. Three recyrstallizations from absolute ethanol give product, m.p. 219220C.

Analysis, Calcd. for C H BrN-C H O C, 58.61; H, 4.69; N, 3.26.

Found: C, 58.82; H, 4.71; N, 3.23.

EXAMPLE 21 l-Chloro-5 H-dibenzo a,d ]cyc1ohepten-5 one A. Phosphorus pentachloride addition complex of 5H-dibenz0-[a,d]cyclohepten-5-one To a solution of 25.0 g. of 10,11-dihydro-5H-dibenzo[a,d]cychohepten-5-one in 2.5 ml. phosphorus oxychloride and 50 ml. dry benzene is added 75 g. phosphorus pentachloride (3 eq.) and the mixture is stirred under reflux for 2.5 hours with protection from moisture. After ca. 15 minutes a clear red solution results and a crystalline complex slowly separates accompanied by evolution of hydrogen chloride. At the end of the reflux period the reaction mixture is chilled to C. and the dark complex is isolated by filtration and washed twice with 25 ml. of dry benzene.

B. l0-Chloro-5H-dibenzo[a,d]cyclohepten-5-one 0.5 G. of the phosphorus addition complex prepared above is heated for one hour. at 100C. in vacuum. The cooled reaction product is then triturated with acetic acid to deposit ,10-chloro-5H-dibenzo[a,d]cyclohepten-5-one, m.p. 1l812lC.; on recrystallization from methanol, m.p. l25-126C.

EXAMPLE 22 5-( 3-Cyclopropylaminopropyl )-5 H-dibenzo[a,d]cycloheptene 5-(3-Iodopropyl)-5H-dibenzo[a,d]cycloheptene, 3.6 g. (0.01 mole), is dissolved in ml. of absolute ethanol. Cyclopropylamine, 3 ml., is added and the mixture allowed to stand overnight at room temperature. Ethanol is evaporated under reduced pressure and the residual solid treated with aqueous sodium hydroxide and extracted into benzene. After washing with water, the benzene layer is shaken thoroughly with several portions of 3 N hydrochloric acid and again washed with water. Evaporation of the benzene under reduced pressure and crystallization of the residual'oily solid from a mixture if isopropyl alcohol and absolute ether gives 5-(3-cyclopropylaminopropyl)-5H-dibenzo-[a,d]cycloheptene hydrochloride as white crystals, m.p. 2l2-2l3C., in a yield of 650 mg. Recrystallization from a mixture of isopropyl alcohol and absolute ether affords an analytical sample, m.p. 211". 2l2C.

ml., is placed in a 1 liter, 3-necked flask fitted with a stirrer and gas inlet tube. The apparatus is cooled in an ice-bath and flushed with dry nitrogen while 40.0 g.

(0.40 mole) of cuprous chloride is added portion-wise with stirring. To the dark blue solution is added ethanol, 300 ml., and then methylmercaptan is bubbled into the cooled solution until precipitation is complete and the supernatant solution becomes yellow. The solid V A is collected and washed by centrifugation withfour portions of dilute ammonium hydroxide solution, followed by four portions of absolute ethanol. The yellow product is dried under reduced pressure at 45-50C.

and finally in a vacuum dessicator over concentrated A sulfuric acid.'The yield of product is 41.4 g. (93%).

B. Preparation of 3-methylmercapto-5H-dibenzo[a,d]-Cyclohepten- 5-one I 3-Bromo-5H-dibenzo[a,d]cyclohepten-5 one, 7.93

g., (0.028 mole), and cuprous methylmercaptide, 4.0 1 A g. (0.036 mole), prepared as described in Step A., are

put in a m1. flask fitted with a stirrer and reflux condenser. Quinoline, 44.8 ml., and pyridine, 4.0 ml., are added and the slurry is heated at 200 C. with stir- 7 ring for 6 hours. The reaction mixture is poured into 6 N. hydrochloric acid, ml., and ice and extracted A with five 150 ml. portions of boiling benzene. The combined extracts are washed with three 200 ml. portions 8 of 3 N. hydrochloric acid. After washing withwater,

the solvent is evaporated under'reduced pressure leaving a brown oil, weight 7.41 g., as residue. The oil is dissolved in absolute methanol, ml., and boiledlwith i 370 mg. decolorizing carbon for 30 minutes. The filtrate is concentrated .to 60 ml. and a yellow solid separates, along with a brown oil. The solid is mechanically I separated from the oil and dried in a vacuum dessicator over concentrated sulfuric acid. The product weighs 2.77 g. and melts at 66.567.5C. The brown oil is evaporatively distilled at l46C./O.l mm. andthe sublimate is crystallized from 25 ml. of absolute methanol to give 2.65 g. of material melting at 66.567.5C. (77% yield).

12.71. Found:C, 76.35; H, 4.6l; S, 12.60.

C. Preparation of 5-(3-dimethylaminopropyl)-5-hydroxy-3-methylmer capto-SH-dibenzo[a,dlcycloheptene The Grignard reagent is prepared from 4.86 g. (0.2 g. atom) of magnesium and 24.34 g. (0.2 mole) of 3- dimethylaminopropyl chloride in 100 ml.of tetrahydrofuran as described in US. Pat. No. 3,046,283. Step g A. of Example 2. The solution is standardized by determination of the magnesium content. A volume of the a solution containing 0.043 mole of Grignard reagent is cooled in an ice-bath and stirred while a solution of 3.- methylmercapto-SH-dibenzo[a,d]cyclohepten-5 one,

5.38 g. (0.0213 mole) in 28 ml. tetrahydrofuran, is

Analysis, Calcd. for c r-1 N110; c, 77.39;.H, 7.4 1

Analysis, Calcd. for C H OS: C, 76.16; H, 4.80; S, i

added over a period of twenty minutes. The reaction mixture is stirred in an ice-bath for 30 minutes and at room temperature for 90 minutes. The bulk of the solvent is then distilled at 45C. under reduced pressure and benzene, 70 ml., is added to the residue. The solution is cooled in an ice-bath and the Grignard adduct is hydrolyzed by the dropwise addition of water, 20 ml., with stirring. The benzene solution is separated and the gelatinous residue is extracted three times with 50 ml. portions of boiling benzene. The combined benzene extracts are extracted with three 45 ml. portions of 0.5 M. citric acid solution and washed once with 50 ml. H O. The combined aqueous solutions are made basic with sodium hydroxide solution and extracted with ether. The combined extracts are washed with water and evaporated under reduced pressure. The yellow solid residue, m.p. 127129C., weighs 6.88 g. (95%). Recrystallization from ethanol-water yields 6.50 g. of product melting at l28l29C.

Analysis, Calcd. for C H NOS: C, 74.29; H, 7.42; N, 4.13.

Found: C, 74.60; H, 7.56; N, 3.94.

D. Preparation of 3-dimethylaminopropyl)-5-hydroxy-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene 5 3-Dimethylaminopropyl )-5-hydroxy-3-methylmercapto-SH-dibenzo[a,d]cycloheptene, 21.53 g. (0.063 mole), is dissolved in glacial acetic acid, 250 ml., and the solution is cooled in an ice-bath while 30% hydrogen peroxide, 25.8 ml., is added dropwise with stirring. After standing at room temperature for 22 hours, the solution is saturated with sulfur dioxide for 1 hour with periodic cooling in an ice-bath. The solution is made basic with N. sodium hydroxide solution, 625 ml., and extracted with three 300 ml. portions of benzene. After washing the combined extracts with water, solvent is distilled under reduced pressure leaving a yellow oily residue, weight 23.20 g. The oil solidifies on standing at room temperature. Four recrystallizations from methanol-water gives 13.22 g. (57%) of product melting at 170-171.5C.

Analysis, Calcd. for C H NO S: C, 67,89; H, 6.78; N, 3.77.

Found: C, 67.72; H, 6.78; N, 3.59.

E. 5-( 3-Dimethylaminopropylidene )-3-methylsulfonyl- 5H-dibenzo[a,d]cycloheptene (mixed geometric isomers) 5 3-Dimethylaminopropyl )-5-hydroxy-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (13.62 g., 0.037 mole) is dissolved in 136 ml. of trifluoroacetic acid. Trifluoroacetic anhydride, 68 ml., is added and the solution heated under reflux for 1 hour in a water-bath at 70C. The dark green solution is cooled and poured into 250 ml. ofice-water. The mixture is rendered alkaline with 10 N sodium hydroxide solution while stirring and cooling and extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and the benzene distilled under reduced pressure. The mixed geometric isomers of 5-(3-dimethylaminopropylidene)-3methylsulfonyl-5H-dibenzo-[a,d]cycloheptene is obtained as a brown oily residue in a yield of 13.19 g. (theory, 13.08 g.).

F. a-Isomer of 5-(3-dimethylaminopropylidene)-3-methyl-sulfonyl- 5H-dibenzo[a,d]cycloheptene Hydrochloride The mixture of geometric isomers is dissolved in alcohol. One-half molar equivalent of dry hydrogen chloride dissolved in absolute alcohol is added and the solvent evaporated on a water-bath under reduced pressure. The residue is taken up in isopropyl alcohol and an equal volume of acetone is added. Absolute ether than is added to incipient cloudiness. The a-isomer separates as the crystalline hydrochloride, and is recrystallized to constant melting point. In one experiment the product so obtained sintered at 217C. and melted at 2l8.52l9.5C., clearing at 220.5C.

Analysis, Calcd. for C H O S'HC1: C, 64.68; H, 6.20; N, 3.59; Cl, 9.09.

Found: C, 64.32; H, 6.35; N, 3.38; Cl, 8.78.

G. B-lsomer of 5-(3-dimethylaminopropylidene )-3-methylsulfonyl- 5Hdibe nzo[a,d]cycloheptene The mother liquors from the separation of the hydro- 25 chloride of the a-isomer are evaporated and treated with one-quarter of a molar equivalent of hydrogen chloride in absolute alcohol. After evaporating the solvent, the residue is treated with isopropyl alcohol and acetone and another crop of solid precipitates with ether as described in Step F. The mother liquors then are evaporated under reduced pressure and the residue shaken with dilute sodium hydroxide and benzene. The benzene layer is separated, washed with water and the benzene distilled under reduced pressure. The base of the B-isomer is covered with hexane and allowed to stand until partially crystalline. The base then is recrystallized to constant melting point from cyclohexane. The product obtained in a typical experiment sintered at 141C., melted at 142.5-143C., clearing at 144C.

Analysis, Calcd. for C ,H NO S: C, 71.36, H, 6.56; N, 3.96.

Found: C, 71.37; H, 6.52; N, 3.97.

EXAMPLE 24 5-( 3 -Methylaminopropylidene )-3-methylsuIfonyl-5 H- dibenzo[a,d]cycloheptene (oz-isomer) EXAMPLE 25 5-( 3-Methylaminopropylidene )-3-methylsulfonyl-5 H- dibenzo[a,d]cycloheptene (B-isomer) By substituting 5-(3-dimethylaminopropylidene)-3- methylsulfonyl-SH-dibenzo[a,d]cycloheptene (B-isoample 6,

mer), (Product of Example 23, Step 6.), for the -(3- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A. and B., 5-(3- methylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (,B-isomer) is obtained in the form of a yellow oil. The product is converted to the hydrogen malcate that melts at 175176C.

Analysis, Calcd. for C H ,NO SC H,,O C, 63.28; H, 5.53; N, 3.08.

Found: C, 63.20; H, 5.39; N, 2.98.

EXAMPLE 26 10,1l-Dihydro-5*(3-methylaminopropylidene)-3- methylsulfonyl-5 H-dibenzo[a,d cycloheptene (ct-isomer) A. Hydrogenation of 5-(3-dimethylaminopropylidene)3-methylsulfonyl- 5H-dibenzo[a,d]cycloheptene (oz-isomer) 5-(3-Dimethylaminopropylidene)-3-methylsulfonyl- 5H-dibenzo[a,d]cycloheptene (ct-isomer), (1.39 g., 0.0039 mole), dissolved in 20 m1. of ethanol, is hydrogenated over Raney nickel at 65C. under an initial hydrogen pressure of 440 p.s.i. The catalyst is separated and the solvent evaporated under reduced pressure. Recrystallization from cyclohexane gives 10,11-dihydro-5-(3-dimethylaminopropylidene )-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (at-isomer), m.p. l21-l2l.5C. (sintered, 120C; cleared, 122.5C.).

Analysis, Calcd. for C ,H NO S: C, 70.95; H, 7.09; N, 3.94.

Found: C, 70.75; H, 7.13; N, 3.84.

B. Demethylation of 10,1 l-dihydro-5-(3-dimethylamino-propylidene)-3 methylsulfonyl-SH-dibenzo[a,dlcycloheptene (Ix-isomer) EXAMPLE 27 10,1l-Dihydro-5-(3-rnethylaminopropylidene)-3' methylsulfonyl-SH-dibenzo[a,d ]cycloheptene (,B-isomer) A. Hydrogenation of 5-(3-dimethylaminopropylidene)-3-methylsulfonyl- 5H-dibenzo[a,d]cycloheptene (B-isomer) The procedure of Example 26, Step A., is employed using the ,B-isomerinstead of the cz-isomer. The B-isomer of 10,11-dihydro-5-(3-methylaminopropylidene)- 3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene is obtained as the crystalline base, m.p. 109-110C. (sintered, 108.5C., cleared, 110.5C.).

Analysis, Calcd. for C i-1 N0 5: c, 70.75; H, 7.09;"

N, 3.94. Found: C, 71.20; H, 6.97; N, 3.88.

B. Dimethylation of 10,11-dihydro-5-(3-dimethylaminopropylidene)-3- methylsulfonyl5H-dibenzo[a,d]cycloheptene (,B-isomer) By substituting 10,11-dihydro-5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (B-isomer) for the 5-(3-dimethylaminoq propylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the. procedure of Ex ample 6, Steps A and B., 10,11-dihydro-5-(3- methylaminopropylidene)-3-"nethylsulfonyl-5H-dibenzo[a,d]cycloheptene (,B-isomer) is obtained in the form of a yellow oil. The product is converted to the hydro chloride that melts at 232.5234.5C. after recrystallization from isopropyl alcohol.

Analysis, Calcd. for C HZgNOzS'HClI C, 63.56;;H, i

Found: C, 63.40; H, 6.30; N, 3.66.

EXAMPLE 28 5-( 3-Methylaminopropyl)3-methylsulfonyl-5H-diben zo[a,d]cycloheptene 3-Methylmercapto-5H-dibenzo[ a,d]cycl0hepten-5-ol 3-Methylmercapto-5H-dibenzo[a,d]cyclohepten- 5one, 27.9 g. (0.11 mole), is dissolved in 500ml. of methanol. The solution is stirred and heated torefluxing while a solution of 14.9 g. (0.276 mole) of potassium borohydride in 150 ml. of water containing 0.2 g

ml. of 10 N. sodium hydroxide is added dropwise. After stirring at reflux for 2 hours, the solution is chilled and the precipitated product collected and washed with methanol yielding, typically, 27 g. (96%).An analytical sample melts at l l7l 185C. after repeated recrystallizations from methanol. Analysis, Calcd. for C H OS:C, 75.58, H, 5.55; Found: C, 74.70; H, 5.56.

B. 5-chloro-3-methylmercapto-5H-dibenzo[ a,d cycloheptene 1 A solution of 18 g. (0.071 mole) of 3-methylmercap4 to-5H-dibenzo[a,d]cyclohepten-5-ol in ml. of dry dioxane is cooled in an ice-bath andsaturated with dry halogen chloride. A solid separates and when precipitation appears to be complete, the mixture is stirred with ml. of petroleum ether and the product collected,

washed with petroleum ether, and dried ,in a vacuum desiccator over potassium hydroxide. The yield of 5-.

chloro-3-methylmercapto-5 H-dibenzo[a,d]cycloheptene is 16 g. (84%), mp. l35138C. The melting point is unchanged by recrystallization from cyclohex-- I ane.

Analysis, Calcd. for C H CIS: C, 70.44; H, 4.80. Found: C, 70.19;H, 4.81.

C. 5-(3-Dimethylaminopropyl)-3-methylmercapto-5H- dibenzo[a,d]cycloheptene The Grignard reagent is prepared from dimethylaminopropyl chloride (0.2 mole) and magnesium (0.2 atom) in 75 ml. of dry tetrahydroluran following the method described in U.S. Pat. No. 2,996,503. A 15 i ml. portion of this solution is cooled in an ice-bath and stirred while a solution of 4.7 g. (0.0172 mole) of chloro-3-methylmercapto-5H-dibenzo/a,d/cycloheptene in 25 ml. of tetrahydrofuran is added dropwise. The usual precautions, such as careful drying of the apparatus and maintaining a nitrogen atmosphere, are observed. After stirring the mixture for 2 hours at room temperature, the bulk of the solvent is distilled at 30C. under reduced pressure and the residue dissolved in benzene. The solution is cooled in an ice-bath and the excess Grignard reagent hydrolyzed by the dropwise addition of water. The benzene layer is decanted and the gelatinous precipitate washed with four 25 ml. portions of boiling benzene. After washing with water, the combined benzene solutions are extracted with 50 ml. of 0.5 M. citric acid. The acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. Evaporation of the washed benzene extract under reduced pressure leaves 5-(3-dimethylaminopropyl)-3-methylmercapto-5H-dibenzo[a,d- ]cycloheptene as the oily residue weighing, typically, 4.2 g. (75%).

D. 5-( 3-Dimethylaminopropyl)-3-methylsulfonyl-5H- dibenzo[a,d ]cycloheptene 5-(3-Dimethylaminopropyl)-3-methylmercapto-5H- dibenzo[a,d]cycloheptene, 1.6 g. (0.005 mole), is dissolved in 16 ml. of glacial acetic acid. The solution is cooled in an ice-bath to 15C. and stirred while hydrogen peroxide, 2 ml. of 30%, is added dropwise. The icebath then is removed and the solution stirred while it warms to room temperature and then allowed to stand for 65 hours. The solution is cooled in an ice-bath and stirred while sulfur dioxide is introduced for 1 hour. After dilution with an equal volume of water and with stirring and cooling, the mixture is rendered alkaline with sodium hydroxide and the oily base extracted into benzene. Solvent is evaporated from the washed benzene extract under reduced pressure, leaving the product as a viscous oily residue in a yield of 1.75 g. (93%). The base may be converted to the hydrogen oxalate salt by treating a solution in ethanol with an equimolar quantity of oxalic acid dissolved in ethanol. 5-(3-Dimethylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d- ]cycloheptene hydrogen oxalate separates as a white crystalline solid, mp. l91192C. dec. The melting point is unchanged by recrystallization from ethanol.

Analysis, Calcd. for C ,H NO S-C H O C, 62.00; H, 6.11; N, 3.15.

Found: C, 61.74; H, 5.95; N, 3.07.

E. 5-(3-Methylaminopropyl)-3-methylsulfonyl-5H-dibenzo-a,d]cycloheptene By substituting 5-(3-dimethylaminopropyl)-3- methylsulfonyl-SH-dibenzo[a,d]cycloheptene for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, Step A., and following substantially the same procedure described in Example 6, Steps A and B., there is obtained 5-(3-methylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene as an oily residue. The base is converted to the hydrogen oxalate salt by treating an ethanolic solution of the base with a excess of oxalic acid in ethanol. Dilution with absolute ether precipitates 5-(3- methylaminopropyl)-3-methylsulfonyl-5H-diben- Y d ll CH CH CH NHR H c CHCHNHR 2 2 2 and acid addition salts thereof wherein R is selected from the group consisting of hydrogen, alkyl having up to 6 carbon atoms, benzyl, or cycloalkyl having up to 8 carbon atoms; Y is selected from the group consisting of hydrogen, chloro, bromo; and X and X are selected from the group consisting of hydrogen, chloro, or bromo.

2. A compound selected from the group consisting of I /il\/ and J CHCH CL NHR CH CH CH NHR and acid addition salts thereof wherein R is selected from the group consisting of hydrogen and alkyl having up to 6 carbon atoms.

3. 5-(3-Aminopropylidene )-10,1 l-dihydro-SH- dibenzo[a,d]cycloheptene.

4. 5-(3-Methylaminopropylidene)-10,1 l-dihydro- 5H-dibenzo[a,dlcycloheptene.

5. 5-(3-Aminopropyl)-l0,ll-dihydro-SH-dibenzo- [a,d]cycloheptene.

6. 5-(3-Methylaminopropyl)-10,1 l-dihydro-SH- dibenzo[a,d]cycloheptene. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF
 2. A compound selected from the group consisting of
 3. 5-(3-Aminopropylidene)-10,11-dihydro-5H-dibenzo(a, d)cycloheptene.
 4. 5-(3-Methylaminopropylidene)-10,11-dihydro-5H-dibenzo(a, d)cycloheptene.
 5. 5-(3-Aminopropyl)-10,11-dihydro-5H-dibenzo-(a,d)cycloheptene.
 6. 5-(3-Methylaminopropyl)-10,11-dihydro-5H-dibenzo(a, d)cycloheptene. 